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New HIV remission case report at AIDS 2020: full report

22 July 2020. Related: Conference reports, Cure-related research, .

Richard Jefferys, TAG

On 7 July 2020, a presentation by Ricardo Diaz at the ongoing virtual International AIDS Conference (AIDS 2020) caused a major splash in the media by reporting that one out of 30 participants in a clinical trial conducted in Brazil has experienced a lack of viral load rebound for a little over a year (64.7 weeks) after interrupting antiretroviral therapy (ART). [1, 2]

The trial was launched in 2015 and involved a complex design in which 30 participants with HIV were divided into six groups of five people each. One group continued on a standard ART regimen and served as controls, while the other five groups received the following additional interventions:

  • Group 2: Dolutegravir and the CCR5 inhibitor maraviroc (which has been to reported to also exert HIV latency-reversing effects). [3]
  • Group 3: Dolutegravir, maraviroc and nicotinamide (a water-soluble form of vitamin B3 that may have HIV latency-reversing activity [4]).
  • Group 4: Dolutegravir, maraviroc and auranofin (an antiproliferative drug).
  • Group 5: Dolutegravir and a dendritic cell therapeutic vaccine.
  • Group 6: Dolutegravir, a dendritic cell therapeutic vaccine, auranofin and nicotinamide.

Results from the trial have been presented on a number of previous occasions, including at AIDS 2018, CROI 2019, and the 2019 HIV Persistence Workshop (see abstract OP 8.6 in the abstract book and the report from NATAP). [5, 6, 7, 8]

Results from participants who received auranofin were also the subject of a published paper last year. Overall, declines in HIV DNA levels (a surrogate measure of the HIV reservoir) were found to be greatest among recipients of the multiple interventions in group six. [9]

The original study design did not include an analytical treatment interruption (ATI), but the protocol was later revised and 25 of the participants underwent an ATI approximately 2.5 years after the end of the 48-week study period (during which the interventions were administered).

The presentation at last year’s HIV Persistence Workshop reported that two participants in group six and one in group three displayed undetectable HIV viral loads after the ATI. However, after around 16 weeks the two people from group six showed evidence of viral load rebound and restarted ART.

The remaining participant from group three was the subject of today’s AIDS 2020 presentation. The individual was diagnosed with HIV infection in October 2012 and started ART two months later. According to an article by Jon Cohen in Science, they estimate the date of HIV acquisition to be around June 2012 (the last previous HIV negative test result was in 2010). [10]

Viral load at ART initiation was relatively low: 20,221 copies/mL.

At the time of entry into the trial in September 2015, viral load was undetectable and the CD4 count 720. Two very low level transient viral load blips occurred while receiving the study interventions but otherwise undetectable levels have been maintained while on ART.

HIV DNA was detectable in rectal tissue and blood samples at the end of the 48-week intervention period. Measurements of blood HIV DNA levels subsequently showed a decline during treatment with regular ART regimens, eventually becoming undetectable immediately prior to the ATI which was initiated in March 2019.

After the ATI, viral load did not rebound and has remained undetectable ever since (the last available measurement at the time of the presentation was from June 22, 2020). Slides showing CD4 count and CD4:CD8 ratio over time indicated a notable decline shortly after the ATI, which is surprising given the apparent lack of viral load rebound in the blood, but no further longitudinal data on these measures was reported.

HIV antibody levels evaluated by the Abbott ARCHITECT antigen/antibody combination assay have declined throughout follow up, with the exception of one possible slight increase immediately after the ATI. Results of a rapid HIV antibody test are now negative (in some media reports this has been mistakenly represented as indicating that no HIV antibodies are detectable, which is not accurate).

The case appears encouraging for HIV cure research, with the caveat that late rebounds in viral load have occurred in some previous examples of HIV remission. Importantly, it’s unclear as yet whether the interventions received during the trial contributed to the outcome; the person may have started ART fairly soon after HIV acquisition and there have been other case reports of early-treated individuals containing viral load for variable periods after ART interruptions.

Notably, of the other 30 study participants, nine received nicotinamide and 14 received dolutegravir and maraviroc. Although it’s unclear whether all of these other participants were among those that underwent ATI, no additional examples of similarly prolonged absence of viral load rebound were observed. This appears to argue against a strong effect of these interventions. Additionally, HIV DNA levels continued to decline long after the cessation of the interventions in the participant who has not rebounded.

Emphasizing the uncertainty about the role of the study drugs is important given that nicotinamide is available over-the-counter as a supplement. At the current time, there is no evidence to suggest that adding dolutegravir, maraviroc and nicotinamide to ART regimens would lead to similar outcomes in other people with HIV.

Further analyses will hopefully shed light on how viral load rebound has so far been prevented, and whether the interventions contributed in some way. Information on HIV-specific T cell responses and the individual’s HLA type could be particularly helpful. The Associated Press article on the research includes the welcome news that Diaz will receive support to conduct a larger 60-person trial, so more robust results should be forthcoming. [11]

Source:
Jefferys R. TAG Bascis Science Blog. (7 July 2020).
https://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2020/07/new-hiv-remission-case-report-at-aids-2020.html

References

  1. Diaz R et al. The first long-term remission of chronic HIV-1 infection without myeloablation? AIDS2020, 6-10 July 2020. Oral abstract OAXLB0105.
    https://cattendee.abstractsonline.com/meeting/9289/presentation/3496
  2. ClinicalTrials.gov. Multi interventional study exploring HIV-1 residual replication: a step towards HIV-1 eradication and sterilizing cure.
    https://www.clinicaltrials.gov/ct2/show/NCT02961829
  3. Maraviroc is associated with latent HIV-1 reactivation through NF-κB activation in resting CD4+ T cells from HIV-infected individuals on suppressive antiretroviral therapy. J Virol. 2018 May 1; 92(9): e01931-17. DOI: 10.1128/JVI.01931-17. (14 Feb 2018).
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899181
  4. Samer S et al. Nicotinamide activates latent HIV-1 ex vivoin ART suppressed individuals, revealing higher potency than the association of two methyltransferase inhibitors, chaetocin and BIX01294. The Brazilian Journal of Infectious Diseases 24(2);150-159. (March – April 2020). DOI: 10.1016/j.bjid.2020.01.005.
    https://www.sciencedirect.com/science/article/pii/S1413867020300192
  5. Diaz RS et al. Auranofin plus nicotinamide impact HIV reservoir among ART suppressed HIV individuals. 22nd International AIDS Conference (AIDS 2018). Poster discussion. WEPDB0105.
    https://www.youtube.com/watch?v=YlHw_yTUNI4&feature=youtu.be&t=8m48s
  6. Diaz RS et al. Randomized trial of impact of multiple interventions ON HIV reservoir: SPARC-7 trial. CROI 2019, 4-7 March 2019, Seattle. Poster abstract 399.
    https://www.croiconference.org/abstract/randomized-trial-impact-multiple-interventions-hiv-reservoir-sparc-7-trial
  7. Diaz RS et al. Post-therapy viral set-point abatement following combined antiproliferative and immune-boosting interventions: results from a randomised clinical trial. 9th International Workshop on HIV Persistence during Therapy 10–13 December 2019, Miami. Abstract OP 8.6. Journal of Virus Eradication 2019; 5 (Supplement 3): 1–58.
    http://viruseradication.com/supplement-details/Abstracts_of_the_9th_HIV_Persistence_During_Therapy_Workshop_10%E2%80%9313_December_2019,_Miami,_Florida,_USA
  8. Psomas CK. Report from 9th HIV Persistance During Therapy Workshop;  Reservoirs & Eradication Strategies Workshop.
    http://www.natap.org/2019/HIV/011320_02.htm
  9. Diaz RS et al. Potential impact of the antirheumatic agent auranofin on proviral HIV-1 DNA in individuals under intensified antiretroviral therapy: Results from a randomised clinical trial. International Journal of Antimicrobial Agents 54(5);592-600. (November 2019).
    https://www.sciencedirect.com/science/article/abs/pii/S0924857919302122
  10. Cohen J. An intriguing—but far from proven—HIV cure in the ‘São Paulo Patient’. Science. (7 July 2020).
    https://www.sciencemag.org/news/2020/07/intriguing-far-proven-hiv-cure-s-o-paulo-patient
  11. Marchione M. Doctors say experimental treatment may have rid man of HIV. Associated Press. (7 July 2020).
    https://apnews.com/32171d5b5edb3babe25ba6edc4b505d6

This report was first posted on 8 July 2020.

Links to other websites are current at date of posting but not maintained.